This laboratory has been working to describe the possible receptor mechanisms responsible for therapeutic and side effects of the estrogenic component of oral contraceptives. We have found the putative estrogen receptor in the mammalian liver. We postulate that interaction of estrogen with liver receptor may contribute to the development of the side effects: development of cholesterol gallstones and of hepatomas: liver synthesis of critical plasma proteins including increasing clotting factors and decreasing clotting inhibitors, (involving in thrombosis) and renin substrate (involved in hypertension). We are finding that the liver system is markedly different than other estrogen target organs. This difference appears to be due to extensive, rapid metabolism of estrogens in the liver. Metabolism diminishes receptor binding of the administered estrogen. Although most metabolites will be inactive, selected metabolites formed in high concentration in the liver may bind to the receptors (e.g. catechol-estrogens). The possibility exists that certain estrogens which may be potent in other target organs will not bind to the receptor in the liver and initiate liver mediated responses because they are rapidly metabolized upon entering the liver parenchymal cell to inactive metabolites. We propose to study: 1) The binding of estrogens to receptors in isolated liver parenchymal cells and in liver in vivo. 2) The human liver for estrogen receptor binding and translocation in vitro. 3) Purification of the estrogen receptor from nuclei of liver from one mammalian species after in vivo administration of an estrogen. 4) Correlation of binding to receptor and responses of the liver to the estrogen. These studies may provide principles of estrogen interaction in the liver which are useful guidelines in the selection of estrogens for testing and use (in combination with a progestin) as potentially safer contraceptives and replacement therapy at menopause.